ANHYDROUS COMPOSITIONS OF mTOR INHIBITORS AND METHODS OF USE

ABSTRACT

Disclosed herein are compositions and methods for topical delivery of mTOR inhibitors. In one embodiment, an anhydrous composition includes one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants. Also disclosed herein are methods to treat skin disorders using such compositions.

PRIORITY PARAGRAPH

This application is a divisional of U.S. patent application Ser. No.15/863,573, filed on Jan. 5, 2018, titled “Anhydrous compositions ofmTOR inhibitors and methods of use”, which claims priority to the U.S.Provisional Application No. 62/443,117, filed on Jan. 6, 2017, titled“Anhydrous compositions of mTOR inhibitors and methods of use”, and eachof which is incorporated herein by reference.

SUMMARY

Disclosed herein are compositions and methods for topical delivery ofmTOR inhibitors. In one embodiment, an anhydrous composition comprisesan effective amount of one or more mTOR inhibitors, one or moresolvents, one or more gelling agents, and one or more antioxidants. Insome embodiments, the mTOR inhibitor is present from about 0.1 wt % toabout 20 wt % of the total composition. In some embodiments, the solventis present from about 1 wt % to about 99.9 wt % of the totalcomposition. In some embodiments, the gelling agent is present fromabout 0.1 wt % to about 5 wt % of the total composition. In someembodiments, the antioxidant is present from about 0.001 wt % to about 1wt % of the total composition.

In additional embodiments, methods of treating a skin disorder in asubject in need thereof comprises topically administering an effectiveamount of an anhydrous composition comprising an effective amount of oneor more mTOR inhibitors, one or more solvents, one or more gellingagents, and one or more antioxidants. In some embodiments, the mTORinhibitor is present from about 0.1 wt % to about 20 wt % of the totalcomposition. In some embodiments, the solvent is present from about 1 wt% to about 99.9 wt % of the total composition. In some embodiments, thegelling agent is present from about 0.1 wt % to about 5 wt % of thetotal composition. In some embodiments, the antioxidant is present fromabout 0.001 wt % to about 1 wt % of the total composition.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts total mean deposition of rapamycin (ng) in the tissue(combined epidermis and dermis) following application of rapamycincompositions (O3, NA21, NA22, NA23, NA17, NA19, NA25, AG14, NA 26, NA24,TD201). Each error bar is determined using 1 standard deviation from themean (n=5).

FIG. 2 depicts total mean amount of rapamycin (ng) recovered fromepidermis and dermis, separately, following application of rapamycincompositions (O3, NA21, NA22, NA23, NA17, NA19, NA25, AG14, NA 26, NA24,TD201). Each error bar is determined using 1 standard deviation from themean (n=5).

FIG. 3 depicts total mean deposition of rapamycin (ng) in the tissue(combined epidermis and dermis) following application of rapamycincompositions (NA22, NA28, NA33, NA34, O11, TD201). Each error bar isdetermined using 1 standard deviation from the mean (n=5).

FIG. 4 depicts total mean amount of rapamycin (ng) recovered fromepidermis and dermis, separately, following application of rapamycincompositions (NA22, NA28, NA33, NA34, O11, TD201). Each error bar isdetermined using 1 standard deviation from the mean (n=5).

DETAILED DESCRIPTION

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

As used in this application and in the claims, the singular forms “a,”“an,” and “the” include the plural forms unless the context clearlydictates otherwise. Additionally, the term “includes” means “comprises.”

As used herein, all claimed numeric terms are to be read as beingpreceded by the term, “about,” which means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore, aclaim to “50%” means “about 50%” and encompasses the range of 45%-55%.

The term “patient” and “subject” are interchangeable and may be taken tomean any living organism which may be treated with compounds of thepresent invention. As such, the terms “patient” and “subject” mayinclude, but is not limited to, any non-human mammal, primate or human.In some embodiments, the “patient” or “subject” is a mammal, such asmice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, primates, or humans. In some embodiments, the patient or subjectis an adult, child or infant. In some embodiments, the patient orsubject is a human.

“Administering” when used in conjunction with the mTOR inhibitor meansto administer mTOR inhibitor to a patient whereby the mTOR inhibitorpositively impacts the tissue to which it is targeted. The mTORinhibitors described herein can be administered either alone or incombination (concurrently or serially) with other pharmaceuticallyactive agents. For example, the mTOR inhibitors can be administered incombination with other anti-cancer or anti-neoplastic agents, or incombination with other therapies for treating skin disorders. In someembodiments, the mTOR inhibitors described herein can also beadministered in combination with (i.e., as a combined composition or asseparate compositions) other therapeutics.

An “effective amount” of a composition is a predetermined amountcalculated to achieve the desired effect, i.e., to ameliorate, preventor improve an unwanted condition, disease or symptom of a patient. Theactivity contemplated by the present methods may include boththerapeutic and/or prophylactic treatment, as appropriate. The specificdose of the agent administered according to this invention to obtaintherapeutic and/or prophylactic effects will, of course, be determinedby the particular circumstances surrounding the case, including, forexample, the compound administered, the route of administration, and thecondition being treated. The effective amount administered may bedetermined by a physician in the light of the relevant circumstancesincluding the condition to be treated, the choice of the compound to beadministered, and the chosen route of administration.

The term “carrier” as used herein encompasses carriers, excipients, anddiluents, meaning a material, composition or vehicle, such as a liquidor solid filler, diluent, excipient, solvent or encapsulating materialinvolved in carrying or transporting a pharmaceutical, cosmetic or otheragent across a tissue layer such as the stratum corneum or stratumspinosum.

The transitional term “comprising,” which is synonymous with“including,” “containing,” or “characterized by,” is inclusive oropen-ended and does not exclude additional, unrecited elements or methodsteps. By contrast, the transitional phrase “consisting of” excludes anyelement, step, or ingredient not specified in the claim. Thetransitional phrase “consisting essentially of” limits the scope of aclaim to the specified materials or steps “and those that do notmaterially affect the basic and novel characteristic(s)” of the claimedinvention. In embodiments or claims where the term comprising is used asthe transition phrase, such embodiments can also be envisioned withreplacement of the term “comprising” with the terms “consisting of” or“consisting essentially of.”

The term “treating” is used herein, for instance, in reference tomethods of treating a skin disorder or a systemic condition, andgenerally includes the administration of a compound or composition whichreduces the frequency of, or delays the onset of, symptoms of a medicalcondition or enhance the texture, appearance, color, sensation, orhydration of the intended tissue treatment area of the tissue surface ina subject relative to a subject not receiving the compound orcomposition. This can include reversing, reducing, or arresting thesymptoms, clinical signs, and underlying pathology of a condition in amanner to improve or stabilize a subject's condition.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The weight percentages disclosed herein may be weight-to-weight orweight-to-volume percentages, as appropriate.

Disclosed herein are anhydrous compositions of mTOR inhibitors. In someembodiments, the anhydrous compositions comprise one or more mTORinhibitors, one or more solvents, one or more gelling agents, and one ormore antioxidants.

In some embodiments, the anhydrous composition of mTOR inhibitor has aCmax of about 120-990 micromolar in the epidermis, and about 36-350micromolar in the dermis. In some embodiments, the anhydrous compositionof mTOR inhibitor has a Tmax of about 15-24 hours in the epidermis. Insome embodiments, the anhydrous composition is considered to bebioequivalent or substantially bioequivalent, as measured by acceptedtopical bioavailability studies, to an anhydrous composition comprisinga mTOR inhibitor as described herein.

In some embodiments, the anhydrous composition comprises at least onemTOR inhibitor. Non-limiting examples of mTOR inhibitors are rapamycin(sirolimus), everolimus, pimecrolimus, ridaforolimus, temsirolimus,zotarolimus, rapamycin prodrug AP-23573, AP-23481, torin-1, torin-2,WYE-354, dactolisib, voxtalisib, omipalisib, apitolisib, vistusertib,gedatolisib, WYE-125132, BGT226, palomid 529, GDC-0349, XL388, CZ415,CC-223, ABT-578, SF1126, PKI-587, INK128, AZD8055, NVPBE235, AZD2014,biolimus A9 (umirolimus), GSK2126458, OSI027, PP121, WYE-687, WAY-600,XL765, PI-103, BEZ235, KU-0063794, Torkinib (PP242), PF-04691502, andpharmaceutically acceptable salts, hydrates, solvates, or amorphoussolid thereof, and combinations thereof.

In some embodiments, mTOR inhibitors also include specific inhibitors ofTOR complex 1, specific inhibitors of TOR complex 2, and the like. Inone embodiment, agents that can be used to inhibit TOR complex 2 includebut are not limited to small molecules, nucleic acids, proteins, andantibodies. Small molecules include but are not limited topyridinonequinolines, pyrazolopyrimidines, and pyridopyrimidines. In afurther embodiment, small molecules that inhibit TOR complexes 1 and 2include Torin 1, Torin 2, torkinib (PP242), PP30, KU-0063794, WAY-600,WYE-687, WYE-354, AZD8055, INK128, OS1027, AZD2014, omipalisib,wortmannin, LY294002, PI-103, BGT226, XL765, and NVP-BEZ235. In afurther embodiment, the inhibitors include but is not limited toantisense oligonucleotide, siRNA, shRNA, and combinations thereof. In afurther embodiment, the agent that inhibits TOR complex 2 would notinhibit TOR complex 1.

In some embodiments, the anhydrous composition may further compriseother compounds regulating mTOR pathway, such as tacrolimus, metformin,and the like.

In some embodiments, the mTOR inhibitor is present from about 0.1 wt %to about 20 wt % of the total composition, about 0.1 wt % to about 15 wt% of the total composition, about 0.1 wt % to about 10 wt % of the totalcomposition, about 0.1 wt % to about 4.5 wt % of the total composition,about 0.1 wt % to about 2 wt % of the total composition, or about 0.1 wt% to about 1 wt % of the total composition, and any individual amount orany ranges between any two of these values. In some embodiments, theweight percentages disclosed herein may be weight-to-weight orweight-to-volume percentages. Non-limiting examples include, about 0.1wt. %, about 0.5 wt. %, about 0.8 wt. %, about 1 wt. %, about 1.5 wt. %,about 2 wt. %, about 2.5 wt. %, about 3 wt. %, about 3.5 wt. %, about 4wt. %, about 4.5 wt. %, about 5 wt. %, about 10 wt. %, about 15 wt. %,or about 20 wt. %. In some embodiments, the mTOR inhibitor is rapamycinand is present from about 0.1 wt % to about 10 wt % of the totalcomposition.

In some embodiments, the compounds regulating the mTOR pathway ispresent from about 0.1 wt % to about 20 wt % of the total composition,about 0.1 wt % to about 15 wt % of the total composition, about 0.1 wt %to about 10 wt % of the total composition, about 0.1 wt % to about 4.5wt % of the total composition, about 0.1 wt % to about 2 wt % of thetotal composition, or about 0.1 wt % to about 1 wt % of the totalcomposition, and any individual amount or any ranges between any two ofthese values. In some embodiments, the weight percentages disclosedherein may be weight-to-weight or weight-to-volume percentages.Non-limiting examples include, about 0.1 wt. %, about 0.5 wt. %, about 1wt. %, about 1.5 wt. %, about 2 wt. %, about 2.5 wt. %, about 3 wt. %,about 3.5 wt. %, about 4 wt. %, about 4.5 wt. %, about 5 wt. %, about 10wt. %, about 15 wt. %, or about 20 wt. %.

In some embodiments, the anhydrous compositions may contain one or moresolvents that facilitates solubilization of mTOR inhibitors. In someembodiments, solvents include alcohols, polyols, amides, esters,propylene glycol ethers and mixtures thereof. Non-limiting examples ofalcohol or polyol include ethanol, isopropanol, butanol, benzyl alcohol,ethylene glycol, propylene glycol, PEG 400, PEG 3350, SR-PEG 400,SR-DMI, oleyl alcohol, castor oil, miglyol 810, liquid paraffin,propylene glycol dicaprylate/dicaprate, butanediols and isomers thereof,glycerol, glycerol triacetate, pentaerythritol, sorbitol, mannitol,Transcutol® P (diethylene glycol monoethyl ether), Transcutol HP,diisopropyl adipate, dimethyl isosorbide, polyethylene glycol,polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcelluloseand other cellulose derivatives, cyclodextrins and cyclodextrinderivatives, and mixtures thereof. Examples of amide include2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof. Examplesof an ester include ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycolmonoacetate, propylene glycol diacetate, ε-caprolactone and isomersthereof, δ-valerolactone and isomers thereof, β-butyrolactone andisomers thereof, and mixtures thereof.

In some embodiments, the solvents include benzyl alcohol, DMSO,diglycol, propylene glycol monocaprylate (Capryol 90), diethylene glycolmonoethylether (Transcutol®), tetrahydrofurfurylalcohol polyethyleneglycol ether (glycofurol), butylene glycol, propylene glycol, diethyleneglycol, triethylene glycol, and combinations thereof. More preferably,in some embodiments, solvents include propylene glycol monocaprylate,benzyl alcohol, tetrahydrofurfurylalcohol polyethylene glycol ether, andcombinations thereof. In some embodiments, the anhydrous compositions donot contain ethanol. In some embodiments, the anhydrous compositionscontain benzyl alcohol less than 10 wt %, less than 8 wt %, less than 6wt %, less than 4 wt %, or less than 2 wt %. In some embodiments, theanhydrous compositions do not contain benzyl alcohol.

In some embodiments, the solvent is present from about 1 wt % to about99.9 wt % of the total composition, about 1 wt % to about 90 wt % of thetotal composition, about 1 wt % to about 80 wt % of the totalcomposition, about 1 wt % to about 70 wt % of the total composition,about 1 wt % to about 60 wt % of the total composition, about 1 wt % toabout 50 wt % of the total composition, about 1 wt % to about 40 wt % ofthe total composition, about 1 wt % to about 30 wt % of the totalcomposition, about 80 wt % to about 99.9 wt % of the total composition,about 85 wt % to about 99.9 wt % of the total composition, about 90 wt %to about 99.9 wt % of the total composition, or about 95 wt % to about99.9 wt % of the total composition. Non-limiting examples include, about1 wt. %, about 25 wt. %, about 40 wt. %, about 50 wt. %, about 60 wt. %,about 75 wt. %, about 80 wt. %, about 85 wt. %, about 90 wt. %, about 92wt. %, about 94 wt. %, about 95 wt. %, about 96 wt. %, about 97 wt. %,about 99 wt. %, or about 99.9 wt. %.

In some embodiments, the anhydrous compositions comprise one or moregelling agents, such as poloxamers and carbomers. Non-limiting examplesof poloxamers are poloxamer P-188, poloxamer P-138, poloxamer P-237,poloxamer P-288, poloxamer P-124, poloxamer P-338, and poloxamer P-407.Other block copolymers, such as poly(ethylene glycol/DL lactideCo-glyceride) poly(□-caprolactum), and hydroxypropyl cellulose(KLUCEL®), glyceryl tris 12-hydroxy stearate, hydroxy stearin, propylenecarbonate, polyvinyl pyrolidine can also be used as gelling agents.Non-limiting examples of carbomers that may be used are carbomer 981,carbomer 934, carbomer 934P, carbomer 940, carbomer 941, carbomer 1342,polycarbophil, and calcium polycarbophil. In a preferred embodiment, thegelling agent is selected from hydroxypropyl cellulose, carbomer 981,carbomer 934P, glyceryl tris 12-hydroxy stearate, hydroxy stearin,propylene carbonate, polyvinyl pyrolidine, and combinations thereof. Insome embodiments, the gelling agent is present from about 0.1 wt % toabout 5 wt % of the total composition, about 0.1 wt % to about 4 wt % ofthe total composition, about 0.1 wt % to about 3 wt % of the totalcomposition, about 0.1 wt % to about 2 wt % of the total composition, orabout 0.1 wt % to about 1 wt % of the total composition.

In some embodiments, the anhydrous compositions comprise one or moreantioxidants, such as ascorbic acid, vitamin E and its derivatives,α-tocopherol, ψ-tocopherol, δ-tocopherol, ascorbyl palmitate, propylgallate (PG), octyl gallate, dodecyl gallate, butylated hydroxy anisole(BHA) and butylated hydroxy toluene (BHT), and D-a-tocopherylpolyethylene glycol 1000 succinate. In some embodiments, the antioxidantis present from about 0.001 wt % to about 1 wt % of the totalcomposition, about 0.001 wt % to about 0.5 wt % of the totalcomposition, about 0.001 wt % to about 0.1 wt % of the totalcomposition, about 0.001 wt % to about 0.05 wt % of the totalcomposition, or about 0.001 wt % to about 0.01 wt % of the totalcomposition.

In some embodiments, the anhydrous composition comprises an effectiveamount of one or more mTOR inhibitors present from about 0.1 wt % toabout 20 wt % of the total composition, one or more solvents presentfrom about 1 wt % to about 99 wt % of the total composition, one or moregelling agents present from about 0.1 wt % to about 5 wt % of the totalcomposition, and one or more antioxidants present from about 0.001 wt. %to about 1 wt. % of the total composition.

In some embodiments, the anhydrous composition comprises an effectiveamount of one or more mTOR inhibitors present from about 0.1 wt % toabout 10 wt % of the total composition, one or more solvents presentfrom about 1 wt % to about 70 wt % of the total composition, and one ormore gelling agents present from about 0.1 wt % to about 4 wt % of thetotal composition, and one or more antioxidants present from about 0.01wt. % to about 1 wt. %. of the total composition.

In some embodiments, the anhydrous composition comprises an effectiveamount of one or more mTOR inhibitors present from about 1 wt % to about10 wt % of the total composition, one or more solvents present fromabout 10 wt % to about 70 wt % of the total composition, one or moregelling agents present from about 1 wt % to about 5 wt % of the totalcomposition, and one or more antioxidants present from about 0.01 wt. %to about 0.5 wt. %. of the total composition.

In some embodiments, the anhydrous composition comprises an effectiveamount of one or more mTOR inhibitors present from about 1 wt % to about5 wt % of the total composition, one or more solvents present from about10 wt % to about 50 wt % of the total composition, one or more gellingagents present from about 1 wt % to about 4 wt % of the totalcomposition, and one or more antioxidants present from about 0.001 wt. %to about 0.01 wt. %. of the total composition.

In some embodiments, the anhydrous compositions comprises an effectiveamount of one or more mTOR inhibitors, one or more solvents, one or moreantioxidants, and no gelling agents.

In some embodiments, the anhydrous compositions of mTOR inhibitorfurther comprises a polymeric surfactant, a moisturizing agent, acooling agent, a rheology modifier, a pH adjusting agent, apreservative, and combinations thereof.

In some embodiments, the anhydrous compositions of mTOR inhibitorcomprises one or more polymeric surfactants. Polymers having surfactantproperties (polymeric surfactant) can be, but are not limited to,hydrophobically modified polyacrylic acid (trade name Pemulen™ TR-I andTR-2), copolymers based on acrylamidoalkyl sulfonic acid and cyclicN-vinylcarboxamides (tradename Aristoflex® AVC), copolymers based onacrylamidoalkyl sulfonic acid and hydrophobically modified methacrylicacid (tradename Aristoflex® HMB), and a homopolymer of acrylamidoalkylsulfonic acid (tradename Granthix APP). Another class of notablepolymeric emulsifier includes hydrophobically-modified, crosslinked,anionic acrylic copolymers, including random polymers, but may alsoexist in other forms such as block, star, graft, and the like. In oneembodiment, the hydrophobically modified, crosslinked, anionic acryliccopolymer may be synthesized from at least one acidic monomer and atleast one hydrophobic ethylenically unsaturated monomer. Examples ofsuitable acidic monomers include those ethylenically unsaturated acidmonomers that may be neutralized by a base. Examples of suitablehydrophobic ethylenically unsaturated monomers include those thatcontain a hydrophobic chain having a carbon chain length of at leastabout 3 carbon atoms. Other materials that may be suitable polymericsurfactants can include ethylene oxide/propylene oxide block copolymers,sold under the trade name PLURONIC®, modified cellulose polymers such asthose modified cellulose polymers described by the trade name KLUCEL®(hydroxypropyl cellulose), monomeric anionic surfactants, monomericamphoteric surfactants, betaine, and combinations thereof. Othersuitable polymeric surfactants include copolymers based onacrylamidoalkylsulfonic acids and cyclic N-vinylcarboxamides and/orlinear N-vinylcarboxamides (e.g., Aristoflex® AVC and Aristoflex® HMB)and a betaine. In preferred embodiments, the polymeric surfactantsinclude poloxamer P-188, poloxamer P-138, poloxamer P-237, poloxamerP-288, poloxamer P-124, poloxamer P-338, poloxamer P-407, D-a-Tocopherylpolyethylene glycol 1000 succinate, Brij 020, and combinations thereof.In some embodiments, the polymeric surfactant is present from about 0.1wt % to about 50 wt % of the total composition, about 0.1 wt % to about40 wt % of the total composition, about 0.1 wt % to about 30 wt % of thetotal composition, about 0.1 wt % to about 20 wt % of the totalcomposition, or about 0.1 wt % to about 10 wt % of the totalcomposition.

In some embodiments, the anhydrous compositions of mTOR inhibitor mayfurther comprise one or more moisturizing agents or an emollientcomponent, for example mineral oil, dimethicone, cyclomethicone,cholesterol, or combinations thereof. In some embodiments, the anhydrouscomposition includes liquid emollients such as polyhydric alcohols,polyols, saccharides, triglycerides, hydrocarbons, silicones, fattyacids, fatty, esters, fatty alcohols, and blends thereof. In someembodiments, the moisturizing agent is present from about 0.5 wt % toabout 10 wt % of the total composition, about 0.5 wt % to about 8 wt %of the total composition, about 0.5 wt % to about 6 wt % of the totalcomposition, about 0.5 wt % to about 4 wt % of the total composition, orabout 0.5 wt % to about 1 wt % of the total composition.

In some embodiments, the anhydrous compositions of mTOR inhibitorcomprise one or more cooling agents, such as L-menthol,p-menthane-3,8-diol, isopulegol, menthoxypropane-1,2,-diol, menthyllactate (such as Frescolat® ML), gingerol, icilin, tea tree oil, methylsalicylate, camphor, peppermint oil, N-ethyl-p-menthane-3-carboxamide,ethyl 3-(p-menthane-3-carboxamido)acetate,2-isopropyl-N,2,3-trimethylbutyramide, menthone glycerol ketal, menthoneglyerine acetal, coolact 10; WS3, WS5, WS23, menthyl glutarate, andmixtures thereof. In some embodiments, the cooling agent is present fromabout 0.5 wt % to about 10 wt % of the total composition, about 0.5 wt %to about 8 wt % of the total composition, about 0.5 wt % to about 6 wt %of the total composition, about 0.5 wt % to about 4 wt % of the totalcomposition, or about 0.5 wt % to about 2 wt % of the total composition.

In some embodiments, the anhydrous compositions disclosed herein doesnot contain water. In some embodiments, the anhydrous compositionsdisclosed herein contains substantially no water. In some embodiments,the anhydrous compositions disclosed herein contain less than 1% ofwater in the total composition. In some embodiments, the anhydrouscompositions disclosed herein contain less than 0.5% of water in thetotal composition. In some embodiments, the anhydrous compositionsdisclosed herein contain less than 0.1% of water in the totalcomposition.

In some embodiments, the anhydrous compositions of mTOR inhibitorsfurther comprise a rheology modifier, a pH adjusting agent, apreservative, and combinations thereof.

The compositions of the present invention also can further comprise apolymer having thickening properties (rheology modifier). In oneembodiment, the polymer having thickening properties can be ahydrophobically modified cross-linked acrylate copolymer (Carbopol®Ultrez 20). Other polymers having similar properties may also be used.Non-limiting examples of polymers having thickening properties caninclude PEG-150 distearate, PEG-7 glyceryl cocoate, PEG-200 hydrogenatedglyceryl palmitate, PEG-120 methyl glucose dioleate, carboxymethylenepolymer, carboxyvinyl polymer, acrylates, C10-C30 alkyl acrylatecrosspolymers, isopropyl myristate, and combinations thereof. In someembodiments, the polymer having thickening properties can comprise about0.1 wt % to about 3 wt %. In another embodiment, polymers havingthickening properties can be present in amounts of 0.4 wt % to about 1.0wt % of the total composition. In one embodiment, the polymer havingthickening properties comprises about 0.5 wt % to about 0.75 wt % of thetotal composition. The thickening polymer can be mixed with thesurfactant polymer in some embodiments.

In some embodiments, the compositions of the present invention canfurther comprise a non-aqueous pH adjusting agent or a non-aqueousbuffering agent, which is present in the composition to neutralizeand/or activate the thickening polymer in order to facilitate theformation of a composition having the desirable rheological qualities.Any anhydrous base or buffer system known in the art and suitable foruse in a skin contact application can be used. In one embodiment, thebase can include triethanolamine, tetrasodium ethylenediaminetetraaceticacid (EDTA), alkali metal hydroxides like sodium hydroxide (NaOH), saltsof weak acids such as ammonium lactate, sodium citrate, sodiumascorbate, or mixtures thereof. The base component also provides utilityin that the pH of the overall composition may be adjusted to a rangefavorable for minimizing irritation of the skin due to pH effects. Insome embodiments compositions of the present invention can also includeanhydrous acids or the acid component of a buffer system, and any acidknown in the art and appropriate for human skin contact may be used.Examples of acids useful in the present composition and commonly used toadjust pH of topical compositions include but are not limited to: citricacid, lactic acid, ascorbic acid, tartaric acid, and hydrochloric acid,and combinations of these and similar acids. In some embodiments, aphosphate buffer system is used in the compositions. In someembodiments, the composition further comprises a phosphate buffer systemand Brij 020. In some embodiments, a phosphate/citrate buffer system isused in the compositions. In some embodiments, the composition containsa phosphate/citrate buffer and Brij 020. Specific examples of the pHlevels of the composition include about pH 4, about pH 4.5, about pH 5,about pH 5.6, about pH 6, about pH 7, about pH 7.4, about pH 8, andranges between any two of these values.

Compositions disclosed herein may further comprise preservatives toprevent the growth of harmful microorganisms. While it is in the aqueousphase that microorganisms tend to grow, microorganisms can also residein the oil phase. As such, preservatives which have solubility in oilare preferably employed in the present compositions. Generally from onetenth of one percent by weight to one percent by weight of preservativesare adequate. The traditional preservatives for cosmetics andpharmaceuticals are alkyl esters of para-hydroxybenzoic acid. Otherpreservatives which have more recently come into use include hydantoinderivatives, propionate salts, cationic surfactants such as benzalkoniumchloride; benzyl alcohol, sorbic acid, and a variety of quaternaryammonium compounds. Cosmetic chemists are familiar with appropriatepreservatives and routinely choose them to satisfy the preservativechallenge test and to provide product stability. Particularly preferredpreservatives for a preferred anhydrous composition of this inventionare phenoxyethanol, phenethyl alcohol, methyl and propylparahydroxybenzoates, imidazolidinyl urea, and quaternium-15. Thepreservatives should be selected having regard for the use of thecomposition and possible incompatibilities between the preservatives andthe other ingredients in the composition.

In some embodiments, the anhydrous compositions are sustained releasecompositions for controlled release of mTOR inhibitors in order todiminish rapid uptake and systemic absorption of the applied agent.Sustained (or controlled) release refers to the gradual release of mTORinhibitors from the composition over a period of time. While there maybe an initial burst phase, in some embodiments, it is preferred that therelease display relatively linear kinetics, thereby providing a constantsupply of the mTOR inhibitor over the release period. The release periodmay vary from about 1 hour to about 8 hours, depending upon the skindisorder and its intended use. The compositions may further comprisevarious biodegradable polymers to facilitate slow release, such aspoly-lactides (PLA), poly-glycolides (PGA), poly butylene succinate(PBS), polyhydroxyalkanoate (PHA), polycaprolactone acid lactone (PCL),polyhydroxybutyrate (PHB), glycolic amyl (PHV), PHB and PHV copolymer(PHBV), and poly lactic acid (PLA)-polyethylene glycol (PEG) copolymers(PLEG). In some embodiments, the preferred polymer is Pluronic® 127.

In some embodiments, the viscosity of the anhydrous compositionsdisclosed herein is generally that of a thick liquid or gel but canreach a paste like consistency. Generally, the viscosity is a minimum ofabout 5,000, 10,000 or 15,000 preferably about 20,000 to a maximum ofabout 12,000,000, 2,000,000 or even about 600,000 cP.

The anhydrous composition of mTOR inhibitors may comprise furtheringredients as required. For example, it may contain a further activeingredient, e.g. a corticosteroid, an antibiotic, an antimycotic, and/oran antiviral agent. Moreover, it may comprise one or more furtherexcipients, such as permeation enhancers (DMSO, Transcutol®, menthol,oleic acid, n-alkanols, 1-alkyl-2-pyrrolidones, N,N-dimethlyalkanamides,and 1,2-alkanediols, etc.), and the like.

In some embodiments, the compositions may further comprise other skincare agents, including, but not limited to, retinol, steroids, sunblock,salicylate, minocycline, antifungals, peptides, antibodies, lidocaine,and the like and combinations thereof. In some embodiments, other skincare agents include N-acyl amino acid compounds including, for example,N-acyl phenylalanine, N-acyl tyrosine, and the like, their isomers,including their D and L isomers, salts, derivatives, and mixturesthereof. An example of a suitable N-acyl amino acid isN-undecylenoyl-L-phenylalanine is commercially available under thetradename SEPIWHITE®. Other skin active agents include, but are notlimited to, Lavandox, Thallasine 2, Argireline NP, Gatuline In-Tense andGatuline Expression, Myoxinol LS 9736, Syn-ake, and Instensyl®,Sesaflash™, N-acetyl D-glucosamine, panthenol (for example, DL panthenolavailable from Alps Pharmaceutical Inc.), tocopheryl nicotinate, benzoylperoxide, 3-hydroxy benzoic acid, flavonoids (for example, flavanone,chalcone), farnesol, phytantriol, glycolic acid, lactic acid, 4-hydroxybenzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid,2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid,trans-retinoic acid, retinol, retinyl esters (for example, retinylpropionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopheroland its esters (for example, tocopheryl acetate: DL-a-tocopheryl acetateavailable from Eisai), azelaic acid, arachidonic acid, tetracycline,ibuprofen, naproxen, ketoprofen, hydrocortisone, acetominophen,resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol,2,4,4′-trichloro-2′-hydroxy diphenyl ether, 3,4,4′-trichlorocarbanilide,octopirox, lidocaine hydrochloride, clotrimazole, miconazole,ketoconazole, neomycin sulfate, theophylline, and mixtures thereof.

One or more sunscreens may be incorporated into the present anhydrouscompositions. A variety of sunscreens may be employed including thep-aminobenzoic acid derivatives such asp-(2-ethylhexyl)dimethylaminobenzoate, and benzophenone derivatives suchas (2-hydroxy-4-methoxyphenyl)phenylmethanone, Mexoryl™ SX, and Mexoryl™XL, terephthalylidene dicamphor sulfonic acid, and drometrizoletrisiloxane. Other non-limiting examples include benzophenones(oxybenzone and sulisobenzone), cinnamates (octylmethoxy cinnamate andcinoxate), salicylates (homomethyl salicylate) anthranilates, TiO₂,avobenzone, bemotrizinol, bisoctrizole, 3-(4-methylbenzylidene)-camphor,cinoxate, diethylamino hydroxybenzoyl hexyl benzoate, dioxybenzone,drometrizole trisiloxane, ecamsule, ethylhexyl triazone, homosalate,menthyl anthranilate, octocrylene, octyl salicylate, iscotrizinol,isopentenyl-4-methoxycinnamate, octyl-dimethyl-p-aminobenzoic acid,octyl-methoxycinnamate, oxybenzone, polysilicone-15, trolaminesalicylate, and ZnO. The exact amount of sunscreen employed in thepresent compositions will vary depending on the degree of protectiondesired from the sun's harmful rays.

The anhydrous compositions of the invention may also comprise one ormore pigments to color the composition, and a fragrance, such asFirmenich and Co. 66.001/NY/G fragrance oil, to make the compositionsoothing to the olfactory system. The amount of these ingredientspresent in the composition will depend on the specific effect desired.

In embodiments, the anhydrous compositions may be in solid dosage formsincluding, but not limited to, topical dosage forms including, but notlimited to, solutions, powders, fluid suspensions, semi-solids,ointments, pastes, creams, lotions, gels, jellies, and foams; andparenteral dosage forms including, but not limited to, solutions,suspensions, and dry powders. The active ingredients can be contained insuch compositions with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,preservatives and the like. Pharmaceutical compositions of the compoundsalso can include suitable solid or gel phase carriers or excipients.Examples of such carriers or excipients include but are not limited tocalcium carbonate, calcium phosphate, gelatin, and polymers such as, forexample, polyethylene glycols.

In some embodiments, the anhydrous compositions disclosed herein may bein the form of a paste, a liquid, lotion, spray, aerosol, powder,ointment, cream, mouthwash, toothpaste, foam, gel, a solid stick, andcombinations thereof. In some embodiments, the compositions disclosedherein are easy to spread, quick absorption, moisturising, non-greasy,non-irritating to patients' skin, aesthetically pleasing to use, and hascooling effect.

In embodiments, the compositions described herein may be formulated as aliquid. Liquid dosage forms for topical administration may includediluents such as, for example, alcohols, glycols, oils, and the like.Such compositions may also include wetting agents or emulsifiers. Insome embodiments, the compositions of embodiments may be formulated asoil-in-water or water-in-oil emulsion. A cream can be a water-in-oil(w/o) emulsion in which an aqueous phase is dispersed in an oil phase,or an oil-in-water (o/w) emulsion in which an oil is dispersed within anaqueous base. An ointment generally refers to a more viscousoil-in-water cream. Traditional ointment bases (i.e. carrier) includehydrocarbons (petrolatum, beeswax, etc.) vegetable oils, fatty alcohols(cholesterol, lanoilin, wool alcohol, stearyl alcohol, etc.) orsilicones. Insoluble solids such as starch, zinc oxide, calciumcarbonate, or talc can also be used in ointments and creams. Gel formsof the compositions described above can be formed by the entrapment oflarge amounts of aqueous or aqueous-alcoholic liquids in a network ofpolymers or of colloidal solid particles. Such polymers or colloids(gelling or thickening agents) are typically present at concentrationsof less than 10% w/w and include carboxymethyl cellulose,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose,sodium alginate, alginic acid, pectin, tragacanth, carrageen, agar,clays, aluminum silicate, carbomers, and the like.

In some embodiments, the mTOR inhibitors in the compositions disclosedherein are stable for extended periods of time. For example, in someembodiments, the mTOR inhibitors in the compositions are stable attemperature ranges from about 4° C. to about 50° C. for a period of12-36 months. In some embodiments, the mTOR inhibitors in thecompositions are stable at temperature ranges from about 4° C. to about45° C. for a period of 12-36 months. In some embodiments, the mTORinhibitors in the compositions are stable at temperature ranges fromabout 4° C. to about 40° C. for a period of 12-36 months. In someembodiments, the mTOR inhibitors in the compositions are stable attemperature ranges from about 4° C. to about 35° C. for a period of12-36 months. in some embodiments, the mTOR inhibitors in thecompositions are stable at temperature ranges from about 4° C. to about30° C. for a period of 12-36 months.

Also disclosed herein are methods to treat a skin disorder in a subject.In some embodiments, a method of treating a skin disorder in a subjectcomprises topically administering an effective amount of an anhydrouscomposition comprising an effective amount of one or more mTORinhibitors, one or more solvents, one or more gelling agents, and one ormore antioxidants.

In some embodiments, a method of treating a skin disorder in a subjectcomprises topically administering an effective amount of an anhydrouscomposition comprising an effective amount of one or more mTORinhibitors, one or more solvents, and one or more antioxidants.

Non-limiting examples of skin disorder that may be treated by theanhydrous compositions include plantar hyperkeratosis, blisters,tuberous sclerosis, seborrheic keratosis, keratosis pilaris,epidermolysis bullosa, multiple minute digitate hyperkeratosis,hyperkeratosis lenticularis perstans, stasis dermatitis, focal acralhyperkeratosis, follicular hyperkeratosis, lichenoid keratoses (lichenplanus, lichen sclerosus), chronic erosive oral lichen,Conradi-Eltinermann, epidermolytic ichthyosis, erythrokeratodermavariabilis, ichthyosis hystrix, KID syndrome, Netherton syndrome,Olmsted syndrome, Refsum disease, Sjogren-Larsson Syndrome, actinickeratosis, pachyonychia congenita, hyperhidrosis, warts, calluses,dermatitis (contact dermatitis, drug-induced dermatitis, allergicdermatitis, nummular dermatitis, perioral dermatitis, neurodermatitis,seborrheic dermatitis, and atopic dermatitis), psoriasis, acne,carbunculosis, cellulitis, furunculosis, granuloma, acanthosisnigricans, athlete's foot, bacterial vaginosis, balanitis,dermatofibrosarcoma protruberans, basal cell carcinoma, squamous cellcarcinoma, melanoma, merkel cell carcinoma, keloid, cystic lymphangioma,Cavernous lymphangioma, venous malformation, epidermal nevi,bromhidrosis, dermatophytosis, candidiasis, onychomycosis, tinea (tineaalba, tinea pedis, tinea unguium, tinea manuum, tinea cruris, tineacorporis, tinea capitis, tinea faciei, tinea barbae, tinea imbricata,tinea nigra, tinea versicolor, tinea incognito), eczema, dyshydroticeczema, decubitous ulcer, ecthyma, erysipalus, erythema multiforme,impetigo, insect bites, genital warts, hemangioma, herpes, hives,hyperhidrosis, filariasis, lentigines, lupus, miliaria, milker'snodules, molluscum contagiosum, myiasis, scabies, cutaneous larvamigrans, furuncular myiasis, migratory myiasis, pediculosis, nevusaraneus, panniculitis, paronychia, pemphigoid, pityriasis, pruritisvulvae, rosacea, trichomoniasis, vaginal yeast infection, vitiligo,xeroderma, angiofibroma, Bannayan-Riley-Ruvalcaba syndrome, basal cellnevus syndrome, Birt-Hogg-Dube syndrome, Blue rubber bleb nevussyndrome, Cowden disease, cutaneous T-cell lymphoma, diffuse microcysticlymphatic malformations, epidermolysis bullosa simplex, extramammarypaget, familial multiple discoid fibromas, Hailey-Hailey disease,infantile hemangiomas, juvenile polyposis syndrome, Kaposi sarcoma,Kaposiform hemangioendothelioma, Keloid scar disease, Lhermitte-Duclossyndrome, metastatic melanoma, Muir-Torre syndrome, neurofibromatosis,nonmelanoma skin cancer, oral graft-versus-host disease, Pemphigusvulgaris, Peutz-Jeghers syndrome, Port-wine stains, Proteus syndrome,Proteus-like Syndrome, refractory hemangioendotheliomas in Maffuccisyndrome, Sturge-weber syndrome, hereditary footpad hyperkeratosis (HFH)in canines, cutaneous sarcoidosis, cutaneous Castleman Disease, BullousPemphigoid, and combinations thereof.

In some embodiments, the skin disorder that is treated is angiofibroma.In some embodiments, the skin disorder that is treated is pachyonychiacongenita. In some embodiments, a symptom of pachyonychia congenita istreated and the symptom is selected from pain, itch or a combinationthereof.

In some embodiments, administration of the composition is by topicalapplication.

In some embodiments, the anhydrous composition of mTOR inhibitors areadministered topically, and the mTOR inhibitor reaches epidermal anddermal layer through absorption. In some embodiments, the topicalapplication of the anhydrous composition does not result in systemicabsorption of the mTOR inhibitors.

In some embodiments, the topical administration of the anhydrouscompositions results in delivery of the mTOR inhibitors to epidermis ofthe skin. In some embodiments, the topical administration of theanhydrous compositions results in delivery of mTOR inhibitors toepidermis and dermis.

In some embodiments, the method of treating a skin disorder involvesadministering topically an anhydrous composition that includes one ormore mTOR inhibitors present from about 0.1 wt % to about 20 wt % of thetotal composition, one or more solvents present from about 1 wt % toabout 99 wt % of the total composition, one or more gelling agentspresent from about 0.1 wt % to about 5 wt % of the total composition,and one or more antioxidants present from about 0.001 wt % to about 1 wt% of the total composition. In some embodiments, the composition mayfurther include a polymeric surfactant, a moisturizing agent, a coolingagent, a rheology modifier, a pH adjusting agent, a preservative, andcombinations thereof. In some embodiments, the anhydrous compositions donot contain gelling agents.

In some embodiments, the anhydrous compositions can be topically appliedto the skin, preferably by manually rubbing the applied amount over theskin to thoroughly coat the skin. The rubbing action preferably is agentle rubbing or massaging for a period of at least about 5 second,preferably about 5 to about 30 seconds to spread all over the skin. Themoisture or water present on the skin may emulsify the anhydrouscomposition due to continuous rubbing and massaging, resulting in theformation of an emulsion in situ on the skin.

Some embodiments of the invention are directed to a method of treatinghair loss in a subject. In some embodiments, the method of treating hairloss includes administering to the subject in need thereof an effectiveamount of an anhydrous composition comprising an effective amount one ormore mTOR inhibitors, one or more solvents, one or more gelling agents,and one or more antioxidants. In embodiments, treatment of diseasesrelated to hair, hair shaft, hair follicles, hair bulbs, oil glands, andcomponents thereof, include, for example, hair loss, dandruff,seborrheic dermatitis, alopecia areata, hair disease, ringworm, tineacapitis, folliculitis, pattern hair loss, telogen effluvium, cradle cap,trichotillomania, traction alopecia, trichorrhexis nodosa, folliculitisdecalvans, head lice infestation, frontal fibrosing alopecia,non-scarring hair loss, pityriasis amiantacea, dissecting cellulitis ofthe scalp, acne keloidalis nuchae, monilethrix, pediculosis, alopeciatotalis, pseudopelade of Brocq, bubble hair deformity, hair casts,hypertrichosis, ingrown hair, monilethrix, premature greying of hair,pattern hair loss, trichorrhexis invaginata, and the like.

The compositions disclosed herein may be applied topically to a selectedarea of the body from which it is desired to reduce hair growth. Forexample, the composition can be applied to the face, particularly to thebeard area of the face, i.e., the cheek, neck, upper lip, and chin. Thecomposition also may be used as an adjunct to other methods of hairremoval including shaving, waxing, mechanical epilation, chemicaldepilation, electrolysis and laser-assisted hair removal. Other actionsthat make their concept appearance are concurrent skin benefits inaddition to hair reduction. The composition can also be applied to thelegs, arms, torso or armpits. The composition is suitable, for example,for reducing the growth of unwanted hair in women. In humans, thecomposition may be applied once or twice a day, or even more frequently,to achieve a perceived reduction in hair growth. Reduction in hairgrowth is demonstrated when, for example, the rate of hair growth isslowed, the need for removal is reduced, the subject perceives less hairon the treated site, or quantitatively, when the weight of hair removed(i.e., hair mass) is reduced.

Some embodiments of the invention are directed to a method of treatingdry eye syndrome in a subject. In some embodiments, the method oftreating dry eye syndrome includes administering to the subject in needthereof an effective amount of an anhydrous composition comprising oneor more mTOR inhibitors, one or more solvents, one or more gellingagents, and one or more antioxidants.

In some embodiments, the anhydrous compositions of the present inventioncan, for example, be applied to a plaster, patch, bandage, or a film. Insome embodiments, topical delivery is aided by the use of ultrasoundtechnology. The ultrasound energy is applied over the tissue and toassist the diffusion of the composition past the tissue.

In embodiments, the compositions disclosed herein can be in the form oftransdermal patches. The transdermal patches can be in any conventionalform such as, for example, a strip, a gauze, a film, and the like. Patchmaterial may be nonwoven or woven (e.g., gauze dressing). Layers mayalso be laminated during processing. It may be nonocclusive orocclusive, but the latter is preferred for backing layers. The patch ispreferably hermetically sealed for storage (e.g., foil packaging). Thepatch can be held onto the skin and components of the patch can be heldtogether using various adhesives. For example, the transdermal patch canbe in the form of a band-aid type device, or it may be packaged in asmall metal or plastic “cup”, which is strapped onto the appropriatesite using an adhesive, tape, or an outer fabric or leather strap,similar to that worn as part of a watch. The entire patch may bedisposable or may be refillable. In some embodiments, the compositionsdisclosed herein can be coated on bandages, mixed with bioadhesives, orincluded in dressings.

In some embodiments, a hand pump may be used to dispense the mTORinhibitor anhydrous compositions. For example, the hand pump may beconfigured to dispense the required dose of mTOR inhibitor within atolerance specified by a corresponding label approved by a governmentregulatory agency. The hand pump may deliver 0.5-10 mL of thecomposition per pump action, such as 1, 2, 3, 4, or 5 mL of thecomposition per pump action. In some embodiments, the mTOR inhibitorcompositions may be packaged along with a pharmaceutically acceptablehand pump.

In some embodiments, the anhydrous compositions may be administered in aconventional manner by any route by which they retain activity. Forexample, the anhydrous composition of mTOR inhibitors may beadministered by routes including, but not limited to, topical,transdermal, or percutaneous. Thus, modes of administration for thecompounds (either alone or in combination with other pharmaceuticals)can be, but are not limited to, sublingual, or by use of vaginal creams,suppositories, pessaries, vaginal rings, rectal suppositories, andpercutaneous and topical forms such as patches and creams, lotions,gels.

The particular quantity of composition administered, of course, will bedetermined by the particular circumstances surrounding its use,including the composition administered, the condition of the skin, theage of the user, the degree of the skin disorder, and similarconsiderations. For example, the dosage may depend on the particularanimal treated, the age, weight, and health of the subject, the types ofconcurrent treatment, if any, and frequency of treatments. Many of thesefactors can be easily determined by one of skill in the art (e.g., bythe clinician). Typically, a single application of the composition willbe applied topically to cover adequately the affected area of the skin.Subsequent applications may be made as needed to deliver the desiredlevel of mTOR inhibitors.

In some embodiments, the composition can be administered one, two,three, four, five or more times each day, and applying can be carriedout for a period of at least 1 month, 2 months, 3 months, 4 months, 6months, 8 months or 12 months.

In some embodiments, the composition may be administered once, asneeded, once daily, twice daily, three times a day, once a week, twice aweek, every other week, every other day, or the like for one or moredosing cycles. A dosing cycle may include administration for about 1week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks.After this cycle, a subsequent cycle may begin approximately 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 weeks later. The treatment regime mayinclude 1, 2, 3, 4, 5, or 6 cycles, each cycle being spaced apart byapproximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

In embodiments, the method of treating a skin disorder comprisingadministering the anhydrous composition described herein, wherein themethod does not further include any additional medical or therapeuticintervention for treatment of the skin disorder.

In embodiments, the method of treating a skin disorder comprisesadministering the anhydrous compositions described herein, wherein themTOR inhibitor is the only active agent administered for treating theskin disorder.

In some embodiments, the methods may include a variety of additionalsteps including, for example, cleaning the surface tissue at the site ofapplying and the like.

In embodiments, the methods may further include descaling or debridingof the tissue surface before, during or after administration of thecompositions described herein. In embodiments, methods for descaling ordebriding tissue surface may include electromagnetic radiation, laser,dermal abrasion, chemical peel, ultrasound, heating, cooling, or by aneedle.

In embodiments, the tissue surface is descaled or debrided withabrasion. Abrasion of the outer layer or epidermis of the skin (dermalabrasion) is desirable to smooth or blend scars, blemishes, or otherskin conditions that may be caused by, for example, acne, sun exposure,and aging. Standard techniques used to abrade the skin have generallybeen separated into two fields referred to as dermabrasion andmicrodermabrasion. Both techniques remove portions of the epidermiscalled the stratum corneum, which the body interprets as a mild injury.The body then replaces the lost skin cells, resulting in a new outerlayer of skin. Additionally, despite the mild edema and erythemaassociated with the procedures, the skin looks and feels smootherbecause of the new outer layer of skin.

In embodiments, the tissue surface is descaled or debrided withmicrodermabrasion. Microdermabrasion refers generally to a procedure inwhich the surface of the skin is removed due to mechanical rubbing by ahandpiece emitting a stream of sand or grit. For example, a handpiececan be used to direct an air flow containing tiny crystals of aluminumoxide, sodium chloride, or sodium bicarbonate. The momentum of the grittends to wear away two to three cell layers of the skin with each passof the handpiece. Alternatively, new “crystal-free” microdermabrasiontechniques utilize a diamond-tipped handpiece without a stream of grit.

In embodiments, the tissue surface is descaled or debrided withelectromagnetic radiation, for instance using a so-called fractionallaser treatment. By way of example, such methods employ electromagneticradiation (EMR) having one or more wavelengths of between approximately1,850 to 100,000 nanometers and with pulse widths of betweenapproximately 1 femtosecond (1×10-15 s) to 10 milliseconds (10×10-3 s)with fluence in the range of from approximately 1 J/cm2 to 300 J/cm2. Inother examples, the tissue is descaled or debrided with electromagneticradiation having one or more wavelengths of between approximately 2,200to 5,000 nanometers. In still other examples, the tissue is descaled ordebrided with electromagnetic radiation having one or more wavelengthsof between approximately 190 to 320 nanometers with fluence in the rangeof from 1 J/cm2 to 300 J/cm2. Optionally, conditions selected fordebriding portions of the tissue minimize the coagulation zone of tissuedamage, for instance by keeping the coagulation zone to a relativelysmall diameter surrounding the ablated void.

Electromagnetic radiation (EMR), particularly in the form of laser lightor other optical radiation, has been used in a variety of cosmetic andmedical applications, including uses in dermatology, dentistry,ophthalmology, gynecology, otorhinolaryngology and internal medicine.For most dermatological applications, EMR treatment can be performedwith a device that delivers the EMR to the surface of the targetedtissue(s). EMR treatment is typically designed to (a) deliver one ormore particular wavelengths (or a particular continuous range ofwavelengths) of energy to a tissue to induce a particular chemicalreaction, (b) deliver energy to a tissue to cause an increase intemperature, or (c) deliver energy to a tissue to damage or destroycellular or extracellular structures, such as for skin remodeling.Examples of devices that have been used to treat the skin duringcosmetic procedures such as skin rejuvenation include the Palomar®LuxIR, the Palomar® 1540, 1440 and 2940 Fractional Handpieces, theReliant Fraxel® SR Laser and similar devices by Lumenis, Alma Lasers,Sciton and many others.

In embodiments, the methods may further include photodynamic therapybefore, during or after administration of the compositions describedherein. Photodynamic therapy is a minimally invasive two-step medicalprocedure that uses photoactivatable drugs called photosensitizers totreat a range of diseases. First, a photosensitizer is administered and,once it has permeated the target tissue, the photosensitizer is thenactivated by exposure to a dose of electromagnetic (usually light)radiation at a particular wavelength. The compositions disclosed hereinmay contain a photosensitizer. In embodiments, any suitablephotosensitizing agent or mixture of agents may be used herein.Generally, these will absorb radiation in the range of from about 380 nmto about 900 nm. As used herein, “photosensitizer” or “photosensitizingagent” preferably means a chemical compound which, when contacted byradiation of a certain wavelength, forms singlet oxygen or thermalenergy. Non-limiting examples of photosensitizers include aminolevulinicacid esters, porphyrins, porphyrin derivatives, bacteriochlorins,isobacteriochlorins, phthalocyanine, naphthalocyanines,pyropheophorbides, sapphyrins, texaphyrins, tetrahydrochlorins,purpurins, porphycenes, phenothiaziniums, and metal complexes such as,but not limited to, tin, aluminum, zinc, lutetium, and tin ethyletiopurpurin (SnET2), and combinations thereof.

The compositions of the present invention can also be administered incombination with other active ingredients, or other compatible drugs orcompounds where such combination is seen to be desirable or advantageousin achieving the desired effects of the methods described herein.

This invention and embodiments illustrating the method and materialsused may be further understood by reference to the followingnon-limiting examples.

EXAMPLES Example 1

An exemplary anhydrous composition is described below:

Component wt % Role tetrahydrofurfurylalcohol 34.55%   drug solventpolyethylene glycol ether Transcutol ® 15% co-solvent propylene glycolmonocaprylate 20% co-solvent Propylene Glycol  5% skin penetrationenhancer/solvent Poloxamer 407 10% surfactant WS5 1.05%  cooling agentrapamycin 1.2%  API cholesterol 0.95%  emollient Silicones 10% emollientKlucel ® 2.25%  gelling agent

Example 2

An exemplary anhydrous composition is described below:

Component wt % Role tetrahydrofurfurylalcohol 29.42%  drug solventpolyethylene glycol ether Transcutol ®   9% co-solvent PEG400  35%co-solvent Propylene Glycol   5% skin penetration enhancer/solvent WS51.05% cooling agent rapamycin  2.4% API Cholesterol 0.90% emollientCyclomethicone  10% emollient Dimethicone   5% emollient Klucel ® 2.23%gelling agent

Example 3

An exemplary anhydrous composition is described below:

Component wt % Role Capryilic/Capric 30.45%    drug solventTriclycerides Transcutol 10%  co-solvent Glycofural 25%  co-solventPropylene Glycol 5% skin penetration enhancer/solvent Isopropylmyristate 8% emollient/thickening agent WS5 1.05%   cooling agentrapamycin 2.2%  API Ascorbyl Palmitate 0.3%  antioxidant Cyclomethicone10%  emollient Dimethicone 5% emollient Carbopol 3% gelling agent

Example 4

An exemplary anhydrous composition (NA 17) is described below:

component Wt % Role Rapamycin 3.26 API Isopropyl alcohol 15 solventPEG400 55.668 solvent Transcutol P 15 penetration enhancer/solventGlycerol 10 solvent Klucel ® 1 gelling agent Propyl gallate 0.05antioxidant Ascorbyl palmitate 0.02 antioxidant a-tocopherol 0.002antioxidant

Example 5

An exemplary anhydrous composition (NA 19) is described below:

component Wt % Role Rapamycin 3.26 API Isopropyl alcohol 15 solventPEG400 55.388 solvent Transcutol P 15 penetration enhancer/solventGlycerol 10 solvent Klucel ® 1 gelling agent Propyl gallate 0.05antioxidant Ascorbyl palmitate 0.02 antioxidant a-tocopherol 0.002antioxidant peppermint oil 0.2 cooling agent menthol 0.08 cooling agent

Example 6

An exemplary anhydrous composition (NA 21) is described below:

component Wt % Role Rapamycin 4.54 API Isopropyl alcohol 15 solventPEG400 44.388 solvent Transcutol P 25 penetration enhancer/solventGlycerol 10 solvent Klucel ® 1 gelling agent Propyl gallate 0.05antioxidant Ascorbyl palmitate 0.02 antioxidant a-tocopherol 0.002antioxidant

Example 7

An exemplary anhydrous composition (NA 22) is described below:

component Wt % Role Rapamycin 3.9 API Isopropyl alcohol 15 solventPEG400 55.3 solvent diisopropyl adipate 15 solvent Glycerol 10 solventKlucel ® 0.75 gelling agent Propyl gallate 0.05 antioxidant Ascorbylpalmitate 0.02 antioxidant a-tocopherol 0.002 antioxidant

Example 8

An exemplary anhydrous composition (NA 23) is described below:

component Wt % Role Rapamycin 4.51 API ethanol 15 solvent PEG400 54.418solvent diisopropyl adipate 15 solvent Glycerol 10 solvent Klucel ® 1gelling agent Propyl gallate 0.05 antioxidant Ascorbyl palmitate 0.02antioxidant a-tocopherol 0.002 antioxidant

Example 9

An exemplary anhydrous composition (NA 24) is described below:

component Wt % Role Rapamycin 2.384 API Isopropyl alcohol 15 solventPEG400 56.548 solvent Propylene glycol 15 penetration enhancer/solventGlycerol 10 solvent Klucel ® 1 gelling agent Propyl gallate 0.05antioxidant Ascorbyl palmitate 0.02 antioxidant a-tocopherol 0.002antioxidant

Example 10

An exemplary anhydrous composition (NA 25) is described below:

component Wt % Role Rapamycin 2.69 API Isopropyl alcohol 15 solventPEG400 26.238 solvent Propylene glycol 15 penetration enhancer/solventTranscutol P 25 penetration enhancer/solvent Diisopropyl adipate 15solvent Klucel ® 1 gelling agent Propyl gallate 0.05 antioxidantAscorbyl palmitate 0.02 antioxidant a-tocopherol 0.002 antioxidant

Example 11

An exemplary anhydrous composition (NA 26) is described below:

component Wt % Role Rapamycin 3.254 API Isopropyl alcohol 15 solventPEG400 47.608 solvent Propylene glycol 15 penetration enhancer/solventTranscutol P 10 penetration enhancer/solvent Glycerol 10 solventKlucel ® 1 gelling agent Propyl gallate 0.05 antioxidant Ascorbylpalmitate 0.02 antioxidant a-tocopherol 0.002 antioxidant

Example 12

An exemplary ointment composition (O3) is described below:

component Wt % Role Rapamycin 4.59 API PEG400 34.34 solvent Transcutol P47.998 penetration enhancer/solvent PEG 3350 13 solvent Propyl gallate0.05 antioxidant Ascorbyl palmitate 0.02 antioxidant a-tocopherol 0.002antioxidant

Example 13

An exemplary aqueous composition (TD201) is described below:

component Wt % Rapamycin 1 water 87.95 Pemulen TR-1 0.28 Carbopol Ultrez10 0.76 Propylene glycol 2.87 Oleic acid 1.43 Mineral oil 0.95Triethanol amine ca. 0.76 (q.s to pH 5-7) Benzyl alcohol 4

Example 14

An exemplary anhydrous composition (NA 28) is described below:

component Wt % Role Rapamycin 3.9 API Isopropyl alcohol 15 solventPEG400 51 solvent Propylene glycol 1.5 penetration enhancer/solventDiisopropyl adipate 15 solvent Glycerol 10 solvent Benzyl alcohol 2solvent Oleyl alcohol 0.75 solvent Klucel ® 0.75 gelling agent Propylgallate 0.05 antioxidant Ascorbyl palmitate 0.02 antioxidanta-tocopherol 0.002 antioxidant

Example 15

An exemplary anhydrous composition (NA 33) is described below:

component Wt % Role Rapamycin 3.9 API PEG400 28.3 solvent Propyleneglycol 15 penetration enhancer/solvent Transcutol P 15 Penetrationenhancer/solvent Diisopropyl adipate 15 solvent Glycerol 10 solventBenzyl alcohol 2 solvent Oleyl alcohol 10 solvent Klucel ® 0.75 gellingagent Propyl gallate 0.05 antioxidant Ascorbyl palmitate 0.02antioxidant a-tocopherol 0.002 antioxidant

Example 16

An exemplary anhydrous composition (NA 34) is described below:

component Wt % Role Rapamycin 3.2 API PEG400 51.7 solvent Propyleneglycol 1.5 penetration enhancer/solvent Transcutol P 15 Penetrationenhancer/solvent Diisopropyl adipate 15 solvent Glycerol 10 solventBenzyl alcohol 2 solvent Oleyl alcohol 0.75 solvent Klucel ® 0.75gelling agent Propyl gallate 0.05 antioxidant Ascorbyl palmitate 0.02antioxidant a-tocopherol 0.002 antioxidant

Example 17

An exemplary ointment composition (O 11) is described below:

component Wt % Role Rapamycin 2.5 API PEG400 43 solvent Propylene glycol1.5 penetration enhancer/solvent Transcutol P 29.45 Penetrationenhancer/solvent Water 7.8 solvent Benzyl alcohol 2 solvent Oleylalcohol 0.75 solvent PEG 3350 13 solvent Propyl gallate 0.05 antioxidantAscorbyl palmitate 0.02 antioxidant a-tocopherol 0.002 antioxidant

Example 18

Ex Vivo Skin Permeation Experiment

Human donor skin was placed between upper and lower compartments. Thelower compartment was filled with receiver fluid. Various rapamycincompositions were applied on the surface of the skin facing the uppercompartment (11 formulations (i.e., O3, NA21, NA22, NA21, NA17, TD201,NA19, NA25, AG14, NA26 and NA24), n=6 replicates, dosage 10 mg/cm²) andleft for 24 hrs. A positive displacement pipette was used to apply theformulation (˜10 mg/cm²) to the plunger of a 1 mL syringe. Theformulation (10+/−0.5 mg) was applied to the skin surface and spreadover the diffusion area using the plunger. Prior to and after theapplication the weight of the plunger was recorded, from which the doseper cell was calculated.

Following the time period, the excess rapamycin compositions were wipedfrom the skin surface and the skin layers were separated into stratumcorneum, epidermis, and dermis. The Stratum corneum was removed from thehuman skin using a tape stripping procedure. The epidermis was separatedfrom the dermis by dry heating at 60° C. for 2 min. Rapamycin wasextracted from each layer by 90:10 v/v ethanol:water solvent mixture,and quantified. The receiver fluid in the lower compartment was alsoanalyzed for the presence of rapamycin.

As would be expected, the greatest amount of rapamycin was found on thesurface of the skin after 24 hours. Further, there appeared to be moreof the drug residing in the epidermis than either the stratum corneum ordermal layer. Furthermore, over time there was an increase in the amountof rapamycin quantified in both the epidermis and dermis. Rapamycin wasnot detected in the receiver fluid at any of the time points across theexperimental period, suggesting that rapamycin did not fully passthrough the skin layers.

As shown in FIGS. 1 and 2, results from the penetration experimentrevealed similarity of epidermal drug recoveries following applicationof all formulations when compared to TD201, with the exception of NA24,where amounts of drug recovered from the skin from TD201 were eightfoldhigher. Significantly higher amounts of drug in the dermis were observedfrom 03 when compared to TD201 (p<0.02), however all other formulationswere statistically comparable but NA21, NA22 and NA23 exhibited higheraverage dermis levels than those observed in TD201. When delivery of thedrug to the total tissue, i.e. the epidermis and dermis in combinationwas considered, all formulations exhibited drug recoveries statisticallysimilar to TD201.

Further, as shown in FIGS. 3 and 4, results of the penetrationexperiment indicated that significantly higher amounts of rapamycin weredelivered to the epidermis following application of NA22, NA33 and NA28when compared to 011 (p<0.05) while all other comparisons werestatistically similar (i.e. TD201 performed similarly to all anhydrousformulations). Furthermore, NA22 was shown to outperform TD201, NA34 and011 when levels of dermal drug delivery were considered, withsignificantly higher deposition in this skin layer than theaforementioned formulations (p<0.05). The results suggest that NA22demonstrated enhanced drug delivery to the dermis and comparabledelivery to the epidermis when compared to the formulation TD201.

In summary, anhydrous compositions showed significant amount ofrapamycin deposition in the skin layers, when compared to aqueouscompositions, AG14 and TD201.

Example 19: Evaluating Topical Bioavailability Dermatopharmacokinetic(DPK) Studies

The dermatopharmacokinetic (DPK) approach is comparable to a blood,plasma, urine PK approach applied to the stratum corneum. DPKencompasses drug concentration measurements with respect to time andprovides information on drug uptake, apparent steady-state levels, anddrug elimination from the stratum corneum based on a stratum corneumconcentration-time curve.

Application and Removal of Test and Reference Products: The treatmentareas will be marked using a template without disturbing or injuring thestratum corneum/skin. The size of the treatment area will depend onmultiple factors including drug strength, analytical sensitivity, theextent of drug diffusion, and exposure time. The stratum corneum ishighly sensitive to certain environmental factors. To avoid bias and toremain within the limits of experimental convenience and accuracy, thetreatment sites and arms will be randomized. Uptake, steady-state, andelimination phases, as described in more detail below, may be randomizedbetween the right and left arms in a subject. Exposure time points ineach phase may be randomized among various sites on each arm. The testand reference products for a particular exposure time point may beapplied on sites to minimize differences. Test and reference productsshould be applied concurrently on the same subjects according to a SOPthat has been previously developed and validated. The premarked siteswill be treated with predetermined amounts of the products (e.g., 5mg/sq cm) and covered with a nonocclusive guard. Occlusion will be usedonly if recommended in product labeling. Removal of the drug productwill be performed according to SOPs at the designated time points, usingmultiple cotton swabs or Q-tips with care to avoid stratum corneumdamage. In case of certain oily preparations such as ointments, washingthe area with a mild soap may be needed before skin stripping. Ifwashing is carried out, it will be part of an SOP.

Sites and Duration of Application: The bioavailability/bioequivalence(BA/BE) study will include measurements of drug uptake into the stratumcorneum and drug elimination from skin. A minimum of eight sites will beemployed to assess uptake/elimination from each product. The time toreach steady state in the stratum corneum will be used to determinetiming of samples. For example, if the drug reaches steady-state inthree hours, 0.25, 0.5, 1 and 3 hours posttreatment may be selected todetermine uptake and 4, 6, 8 and 24 hours may be used to assesselimination. A zero time point (control site away from test sites) oneach subject will be selected to provide baseline data. If thetest/reference drug products are studied on both forearms, randomlyselected sites on one arm may be designated to measure druguptake/steady-state. Sites on the contralateral arm may then bedesignated to measure drug elimination. During drug uptake, both theexcess drug removal and stratum corneum stripping times are the same sothat the stratum corneum stripping immediately follows the removal ofthe excess drug. In the elimination phase, the excess drug will beremoved from the sites at the steady-state time point, and the stratumcorneum will be harvested at succeeding times over 24 hours to providean estimate of an elimination phase.

Collection of Sample: Skin stripping proceeds first with the removal ofthe first 1-2 layers of stratum corneum with two adhesive tapesstrip/disc applications, using a commercially available product (e.g.,D-Squame, Transpore). These first two tape-strip(s) contain thegenerally unabsorbed, as opposed to penetrated or absorbed, drug andtherefore will be analyzed separately from the rest of the tape-strips.The remaining stratum corneum layers from each site will be stripped atthe designated time intervals. This is achieved by stripping the sitewith an additional 10 adhesive tape-strips. All ten tape strips obtainedfrom a given time point will be combined and extracted, with drugcontent determined using a validated analytical method. The values willbe generally expressed as amounts/area (e.g., ng/cm2) to maintainuniformity in reported values. Data may be computed to obtain full drugconcentration-time profiles, Cmax-ss, Tmax-ss, and AUCs for the test andreference products.

Procedure for Skin Stripping:

To assess drug uptake: The test and/or reference drug products will beapplied concurrently at multiple sites. After an appropriate interval,the excess drug from a specific site will be removed by wiping threetimes lightly with a tissue or cotton swab. Using information from thepilot study, the appropriate times of sample collection to assess druguptake will be determined. The application of adhesive tape two timeswill be repeated, using uniform pressure, discarding these first twotape strips. Stripping will be continued at the same site to collect tenmore stratum corneum samples. Care will be taken to avoid contaminationwith other sites. The procedure will be repeated for each site at otherdesignated time points. The drug will be extracted from the combined tenskin strippings and the concentration will be determined using avalidated analytical method. The results will be expressed as amount ofdrug per square cm treatment area of the adhesive tape.

To assess drug elimination: The test and reference drug product will beapplied concurrently at multiple sites chosen based on the results ofthe pilot study. Sufficient exposure period to reach apparentsteady-state level will be allowed. Excess drug from the skin surfacewill be removed as described previously, including the first two skinstrippings. The skin stripping samples will be collected using tensuccessive tape strips at time intervals based on the pilot study anddrug content will be analyzed.

Metrics and Statistical Analyses: A plot of stratum corneum drugconcentration versus a time profile will be constructed to yield stratumcorneum metrics of Cmax, Tmax and AUC. The two one-sided hypotheses atthe α=0.05 level of significance will be tested for AUC and Cmax byconstructing the 90 percent confidence interval (CI) for the ratiobetween the test and reference averages. Individual subject parameters,as well as summary statistics (average, standard deviation, coefficientof variation, 90% CI) will be reported. For the test product to be BE,the 90 percent CI for the ratio of means (population geometric meansbased on log-transformed data) of test and reference treatments willfall within 80-125 percent for AUC and 70-143 percent for Cmax.

In Vivo Dermal Open Flow Microperfusion

In dermal open-flow microperfusion (dOFM), a thin, hollow tube will beinserted just under the skin surface, running through a section of theskin a few inches wide and then exiting. A liquid similar to body fluidwill be injected into the tubing; a portion of the tube under the skinis porous, so any drug that has been applied and absorbed through theskin's outer layer enters the flowing liquid, which will be thencollected for analysis. dOFM can reliably measure the changing amountsof drug in the skin after topical application of a dermatological drugproduct.

What is claimed is:
 1. A topical anhydrous gel composition comprising:2.5 wt % to about 4.5 wt % of rapamycin or a pharmaceutically acceptablesalt thereof, based upon the total weight of the composition, about 80wt % to about 97 wt % of a solvent, based upon the total weight of thecomposition, wherein the solvent is about 1 wt % to about 30 wt %diisopropyl adipate based upon the total weight of the composition,about 1 wt % to about 30 wt % glycerol based upon the total weight ofthe composition, about 40 wt % to about 60 wt % polyethylene glycolbased upon the total weight of the composition, and about 1 wt % toabout 30 wt % isopropyl alcohol, based upon the total weight of thecomposition, about 0.1 wt % to about 5 wt % of a gelling agent, basedupon the total weight of the composition, about 0.001 wt % to about 1 wt% of an antioxidant, based upon the total weight of the composition, andoptionally an additional pharmaceutically acceptable excipient, whereina total weight of the composition is 100 wt %, and wherein the anhydrousgel composition has a pH of about 4 to about
 6. 2. The topical anhydrousgel composition of claim 1, wherein the gelling agent is selected fromthe group consisting of hydroxypropyl cellulose, carbomer 981, carbomer934P, glyceryl tris 12-hydroxy stearate, hydroxy stearin, propylenecarbonate, polyvinyl pyrrolidine, and combinations thereof.
 3. Thetopical anhydrous gel composition of claim 1, wherein the antioxidant isselected from the group consisting of ascorbyl palmitate, propylgallate, a-tocopherol, and combinations thereof.
 4. The topicalanhydrous gel composition of claim 1, wherein the composition furthercomprises a polymeric surfactant, a moisturizing agent, a cooling agent,a rheology modifier, a preservative, and combinations thereof.
 5. Thetopical anhydrous gel composition of claim 1, wherein the compositionfurther comprises a skin care agent selected from the group consistingof cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters, andcombination thereof.
 6. The topical anhydrous gel composition of claim1, wherein the composition comprises: rapamycin from about 3 wt % toabout 4.5 wt % of the composition; polyethylene glycol from about 40 wt% to about 60 wt % of the composition; isopropyl alcohol at about 15 wt% of the composition; diisopropyl adipate at about 15 wt % of thecomposition; glycerol at about 10 wt % of the composition; the gellingagent from about 0.1 wt % to about 1 wt % of the composition; theantioxidant from about 0.001 wt % to about 0.1 wt % of the composition;and wherein the additional pharmaceutically acceptable excipient is abuffer.
 7. The topical anhydrous gel composition of claim 6, wherein thecomposition comprises: rapamycin at about 3.9 wt % of the composition;isopropyl alcohol at about 15 wt % of the composition; polyethyleneglycol at about 55.3 wt % of the composition; diisopropyl adipate atabout 15 wt % of the composition; glycerol at about 10 wt % of thecomposition; wherein the gelling agent is hydroxypropyl cellulose;wherein the antioxidant is selected from propyl gallate, ascorbylpalmitate, and alpha-tocopherol; and a buffer.
 8. The topical anhydrousgel composition of claim 7, wherein the anhydrous gel compositioncomprises: rapamycin at about 3.9 wt % of the composition; isopropylalcohol at about 15 wt % of the composition; polyethylene glycol atabout 55.3 wt % of the composition; diisopropyl adipate at about 15 wt %of the composition; glycerol at about 10 wt % of the composition;hydroxypropyl cellulose at about 0.75 wt % of the composition; propylgallate at about 0.05 wt % of the composition; ascorbyl palmitate atabout 0.02 wt % of the composition; alpha-tocopherol at about 0.002 wt %of the composition; and a buffer.
 9. The topical anhydrous gelcomposition of claim 1, wherein the composition has a pH of about 4.5 toabout
 5. 10. The topical anhydrous gel composition of claim 1, whereinthe composition has a viscosity of about 5000 cP to about 20,000 cP. 11.The topical anhydrous gel composition of claim 1, wherein the rapamycinor pharmaceutically acceptable salt thereof is stable in the compositionat a temperature of about 4° C. to about 40° C. for a period of 12 to 36months.